Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

Tanaka, Masaru; Bohár, Zsuzsanna; Vécsei, László

doi:10.3390/molecules25030564

Cited by 86 publications

(113 citation statements)

References 151 publications

(163 reference statements)

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“…Relatively significant symptoms are autonomic dysfunction including arrythmia, blood pressure irregularity, asymmetric sweating, and incontinence and psychobehavioral manifestations including dementia, depression, anxiety, paranoia, and psychosis. The non-motor symptoms may appear in early stages of the disease and even before the appearance of classical motor symptoms [1][2][3] burden on the aging societies. The prevalence of PD is approximately 0.2% on average in the general population, but it is increasing with age up to 1.9% [4].…”

Section: Introductionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

Török¹,

Maszlag-Török²,

Molnár³

et al. 2020

Preprint

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Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

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Section: Introductionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

Török¹,

Maszlag-Török²,

Molnár³

et al. 2020

Preprint

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“…3-HK and QA are agonists at the NMDA receptor. QA is converted to NAD + , which is a feedback inhibitor of TDO [95] (Figure 2). , which also convert 3-HK to xanthurenic acid (XA).…”

Section: The Etiological Links Behind Neurodegenerative Diseases: Trymentioning

confidence: 99%

“…The pro-inflammatory cytokines, IFN-α, IL-1β, IFN-γ, and TNF-α, activate IDO 1, while the anti-inflammatory cytokines, IL-2, IL-4, IL-10, and TGF-β, through IFN-γ, inhibit IDO 1 [93]. IDO 2 has a pro-inflammatory role, contributing to autoantibody production [95]. In addition, IDO-activated cells can alter the cytokine production of APCs to anti-inflammatory cytokines, TGF-β and IL−10, from pro-inflammatory cytokine, IL-12 [117].…”

Section: Kynurenine Pathway Enzyme Activitiesmentioning

confidence: 99%

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Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Tanaka

Toldi

Vécsei

2020

IJMS

186

197

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.

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“…The oxidative state is induced by oxidative stressors either derived from xenobiotics or produced from the activities of oxidative enzymes and essential cellular constituents [ 35 ] ( Figure 1 a). Oxidative stressors are linked to the aging process, neurologic disease, and psychiatric disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), MS, amyotrophic lateral sclerosis (ALS), and depression [ 36 , 37 , 38 , 39 , 40 ].…”

Section: Oxidative Stressmentioning

confidence: 99%

Monitoring the Redox Status in Multiple Sclerosis

Tanaka

Vécsei

2020

Biomedicines

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Worldwide, over 2.2 million people suffer from multiple sclerosis (MS), a multifactorial demyelinating disease of the central nervous system. MS is characterized by a wide range of motor, autonomic, and psychobehavioral symptoms, including depression, anxiety, and dementia. The blood, cerebrospinal fluid, and postmortem brain samples of MS patients provide evidence on the disturbance of reduction-oxidation (redox) homeostasis, such as the alterations of oxidative and antioxidative enzyme activities and the presence of degradation products. This review article discusses the components of redox homeostasis, including reactive chemical species, oxidative enzymes, antioxidative enzymes, and degradation products. The reactive chemical species cover frequently discussed reactive oxygen/nitrogen species, infrequently featured reactive chemicals such as sulfur, carbonyl, halogen, selenium, and nucleophilic species that potentially act as reductive, as well as pro-oxidative stressors. The antioxidative enzyme systems cover the nuclear factor erythroid-2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway. The NRF2 and other transcriptional factors potentially become a biomarker sensitive to the initial phase of oxidative stress. Altered components of the redox homeostasis in MS were discussed in search of a diagnostic, prognostic, predictive, and/or therapeutic biomarker. Finally, monitoring the battery of reactive chemical species, oxidative enzymes, antioxidative enzymes, and degradation products helps to evaluate the redox status of MS patients to expedite the building of personalized treatment plans for the sake of a better quality of life.

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Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

Cited by 86 publications

References 151 publications

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Monitoring the Redox Status in Multiple Sclerosis

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